The n e w e ng l a n d j o u r na l of m e dic i n e

Cl inic a l I m pl ic a t ions of B a sic R e se a rch

Elizabeth G. Phimister, Ph.D., Editor

The Link between Hematopoiesis and Atherosclerosis

Menno P.J. de Winther, Ph.D., and Esther Lutgens, M.D., Ph.D.

The decrease in the incidence of cardiovascular
disease and the improved prognosis in persons
with a diagnosis of cardiovascular disease are due,
in part, to the development of new treatments
based on accrual of knowledge about disease
mechanisms. More specifically, the introduction
of lipid-lowering therapies such as 3-hydroxy-
3-methylglutaryl coenzyme A (HMG-CoA) reduc-
tase inhibitors (statins) and proprotein convertase
subtilisin–kexin type 9 (PCSK9) inhibitors as well
as changes in lifestyle have reduced the risk of
cardiovascular disease by an impressive 25 to 30%
since the 1960s and 1970s. However, cardiovas-
cular disease remains a major cause of disability
and death in the Western world, and new strate-
gies to lower the large residual risk of cardiovas-
cular disease are needed.
There is mounting evidence that atherosclero-
sis is driven not just by dyslipidemia but also by
inflammation. Experimental studies have repeat-
edly proved that inflammation has a role in
atherosclerosis, and the Canakinumab Antiinflam-
matory Thrombosis Outcomes Study (CANTOS)
provided clinical data showing that inflamma-
tion is an important driver of atherosclerotic car-
diovascular disease. The results of that study,
which were published in 2017, showed that tar-
geting inflammation with an antibody against
interleukin-1β led to a lower incidence of recur-
rent cardiovascular events than placebo.1
Inflammation in atherosclerosis is manifested
by an increased presence of immune cells and
inflammatory mediators in the atherosclerotic
plaque, arterial wall, and lymphoid tissues, as well
as in the circulation. Several studies have shown
that the systemic proinflammatory condition in
cardiovascular disease originates at an early stage
of hematopoiesis in the hematopoietic stem and
progenitor cells (HSPCs) that eventually differ-
entiate into and renew the myeloid-cell, lym-
phoid-cell, and erythroid-cell lineages of the bone
marrow.
A direct link between dyslipidemia and HSPC
activation has been reported. Hypercholesterol-
emia causes HSPCs to proliferate, leading to
leukocytosis and atherosclerosis in both animal
models and humans. In fact, studies have indicated
an appreciable regulatory role for cholesterol ef-
flux pathways in the mobilization of HSPCs from
the bone marrow.2
Gu and colleagues3 recently reported on some
molecular determinants underlying this link. They
engineered zebrafish that were deficient in the
cholesterol efflux–mediating protein apolipopro-
tein A-I binding protein 2 (Aibp2). In these fish,
there were fewer HSPCs from the hemogenic en-
dothelium in the dorsal aorta, the site where one
of the first waves of hematopoiesis takes place,
than in the control zebrafish. Because Aibp2
augments the capacity of high-density lipoprotein
to accept cholesterol, the authors hypothesized
that a cholesterol metabolism pathway controls
the emergence of HSPCs. Cholesterol synthesis
is dependent on the master transcription factor
sterol regulatory element–binding protein 2
(Srebp2), which is produced as an endoplasmic
reticulum precursor and is activated on cholesterol
depletion and excess cholesterol efflux. Zebrafish
deficient in the orthologue (fish equivalent) of
Srebp2 had the same deficiency of HSPC emer-
gence from the hemogenic endothelium as the
Aibp2-deficient fish. As a next step, the authors
investigated whether Aibp2 could regulate Srebp2
activity, and this was indeed the case. Cholesterol
efflux mediated by Aibp2 results in the activation
of Srebp2, and Aibp2 thus controls the emergence
of HSPC through Srebp2.
The key role of the Notch family in the speci-
fication of hematopoietic stem cells inspired the
scientists to investigate the effects of Aibp2 and

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A Postulated Mechanism in Zebrafish B Postulated Mechanism in Humans

BLOOD-VESSEL LUMEN
Aibp2 AIBP2 BLOOD-VESSEL LUMEN
HDL
HDL

Cholesterol Efflux of
cholesterol Cholesterol ↑ Efflux of
cholesterol

SREBP2
Lower intracellular HEMOGENIC
cholesterol levels ENDOTHELIAL HEMOGENIC
CELL ENDOTHELIAL
↑ SREBP2 CELL
activation
Golgi
Srebp2
Srebp2 apparatus
activation

Endoplasmic ↑ NOTCH
reticulum
BONE MARROW

↑ HSPC expansion

NUCLEUS

↑ Immune cells
Srebp2 Srebp2 and inflammation

DNA

Atherosclerotic Cardiovascular Disease

Proteins that Notch ↑

regulate cholesterol
metabolism LDL
Foam cell

BONE MARROW

↑ Lipid influx

HSPC expansion

ATHEROSCLEROTIC
ARTERY WALL

Figure 1. Hematopoietic Sequelae of Cholesterol Metabolism.

On the basis of their studies of zebrafish and mouse models, Gu et al.3 recently described a mechanistic link between cholesterol me-
tabolism and inflammation. As shown in Panel A, they found that apolipoprotein A-I binding protein 2 (Aibp2) facilitates cholesterol
efflux from the hemogenic endothelium in the bone marrow by increasing the acceptance of cholesterol by high-density lipoprotein
(HDL). In parallel, the endoplasmic reticulum senses cholesterol lowering, which triggers activation of the transcription factor sterol
regulatory element–binding protein 2 (Srebp2). This transcription factor, in turn, binds DNA motifs in the regulatory elements of choles-
terol metabolism genes, in addition to Notch, thereby facilitating transcription of these genes. Notch induces an expansion of the pool
of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. As shown in Panel B, in persons with dyslipidemia, levels of
activated SREBP2 and NOTCH and numbers of HSPCs are elevated; this is consistent with dyslipidemia aggravating an inflammatory
response initiated in the bone marrow. LDL denotes low-density lipoprotein.

Srebp2 on the Notch-signaling pathway. They ob- enriched in Notch and in genes regulating choles-
served that deficiency of Aibp2 and Srebp2 down- terol synthesis. These findings revealed that path-
regulated Notch signaling and that the Srebp2- ways of hematopoiesis and cholesterol metabolism
binding DNA sequence (or motif) was highly are closely linked and control each other.

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 Clinical Implications of Basic Research

These data prompted the authors to investi-
gate whether the mechanism they identified in
developmental hematopoiesis is also relevant to
adult hematopoiesis, especially in relation to hy-
percholesterolemia. They found that in humans,
low-density lipoprotein levels correlated with the
proportion of HSPCs in blood and that SREBP2
and NOTCH are activated and up-regulated in
HSPCs isolated from persons with hypercholes-
terolemia. This suggests that the SREBP2-regu-
lated NOTCH signaling also orchestrates HSPC
homeostasis in persons with hypercholesterolemia.
Gu et al. have thus uncovered a cholesterol me-
tabolism pathway governing HSPC emergence in
the development as well as in the expansion of
sons with atherosclerotic cardiovascular disease
have an inflammatory constitution, as reflected
by elevated levels of high-sensitivity C-reactive
protein, and they have no or well-controlled dys-
lipidemia; this suggests the existence of other
mechanisms that promote inflammation but not
dyslipidemia. The most notable aspect of the
study by Gu and colleagues is the implication of
“cholesterol metabolism” genes in the biologic
makeup of HSPCs. These findings provide sup-
port for the hypothesis that cholesterol metabo-
lism is a driver of inflammation in cardiovascu-
lar disease.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

the numbers of HSPCs in hypercholesterolemia
(Fig. 1).
Have they uncovered the mechanism linking
dyslipidemia and inflammation in atheroscle-
rosis? This study certainly teaches us that cho-
lesterol metabolism and inflammation are in-
terconnected in the bone marrow environment
through the transcription factor SREBP2. In ad-
dition, it is plausible that targeting some aspect
of the AIBP2–SREBP2–NOTCH axis could be a
therapeutic strategy to ameliorate both dyslip-
idemia and inflammation in cardiovascular dis-
ease. However, a substantial percentage of per-
From the Department of Medical Biochemistry, Amsterdam
Cardiovascular Sciences, Amsterdam University Medical Cen-
ters, University of Amsterdam, Amsterdam; and the Institute
for Cardiovascular Prevention, Ludwig Maximilians University,
Munich, Germany.
1. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory
therapy with canakinumab for atherosclerotic disease. N Engl J
Med 2017;​377:​1119-31.
2. Yvan-Charvet L, Pagler T, Gautier EL, et al. ATP-binding cas-
sette transporters and HDL suppress hematopoietic stem cell
proliferation. Science 2010;​328:​1689-93.
3. Gu Q, Yang X, Lv J, et al. AIBP-mediated cholesterol efflux
instructs hematopoietic stem and progenitor cell fate. Science
2019;​363:​1085-8.
DOI: 10.1056/NEJMcibr1901397
Copyright © 2019 Massachusetts Medical Society.

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